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Nitroreductases and Glutathione Transferases That Act on 4-Nitroquinoline 1-Oxide and Their Differential Induction by Butylated Hydroxyanisole in Mice¹

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199

These studies concern the initial steps in 4-nitroquinoline 1-oxide (4NQO) metabolism in relation to mechanisms of anticarcinogenesis. Butylated hydroxyanisole (BHA) administration by a protocol known to inhibit the pulmonary tumorigenicity of 4NQO in A/HeJ mice enhanced hepatic and pulmonary activities for 4NQO metabolism by two major pathways, conjugative detoxification and nitroreductive activation. High-performance liquid chromatography analysis showed approximate doubling of two types of glutathione transferase subunits with 4NQO-conjugating activity in livers of BHA-treated mice. Similar increases were observed in hepatic 4NQO-conjugating activity and in V_max, while K_m for 4NQO was 39 to 43 µM. Pulmonary 4NQO-glutathione transferase activity increased 24 to 29%. DT diaphorase activity toward 4NQO was elevated 3.3-fold in livers and 2.7-fold in lungs of BHA-treated mice. However, the predominant 4NQO reductase of liver and lung was dicumarol resistant, had a strong preference for NADH, and showed little if any response to BHA. This M_r 200,000 enzyme, partially purified from livers of Swiss mice, exhibited the stoichiometry of 2-NADH/4NQO expected for reduction of 4NQO to 4-hydroxyaminoquinoline 1-oxide. Its high affinity for 4NQO (K_m, 15 µM) signified a much greater influence on 4NQO metabolism than DT diaphorase (K_m 208 µM). The dicumarol-resistant 4NQO reductase differed from several known cytosolic nitroreductases. The results suggest that protection by BHA may result from alteration of the balance between 4NQO activation and conjugation.

¹ Supported by Grant BE-65B from the American Cancer Society.

² Present address: Department of Biochemistry, University of Tennessee-Memphis, 800 Madison Avenue, Memphis, TN 38163.

³ To whom requests for reprints may be addressed, at Department of Biochemistry and Molecular Biology, Slot 516, U. A. M. S., 4301 W. Markham Street, Little Rock, AR 72205-7199.

Received 7/26/91. Accepted 10/18/91.